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BACKGROUND: Most solid tumours contain regions of sub-optimal oxygen concentration (hypoxia). Hypoxic cancer cells are more resistant to radiotherapy and represent the most aggressive fraction of a tumour. It is therefore essential that strategies continue to be developed to target hypoxic cancer cells. Inhibition of the DNA damage response (DDR) might be an effective way of sensitising hypoxic tumour cells to radiotherapy. METHODS: Here, we describe the cellular effects of pharmacological inhibition of the apical DDR kinase ATR (Ataxia Telangiectasia and Rad 3 related) with a highly selective inhibitor, VE-821, in hypoxic conditions and its potential as a radiosensitiser. RESULTS: VE-821 was shown to inhibit ATR-mediated signalling in response to replication arrest induced by severe hypoxia. In these same conditions, VE-821 induced DNA damage and consequently increased Ataxia Telangiectasia Mutated-mediated phosphorylation of H2AX and KAP1. Consistently, ATR inhibition sensitised tumour cell lines to a range of oxygen tensions. Most importantly, VE-821 increased radiation-induced loss of viability in hypoxic conditions. Using this inhibitor we have also demonstrated for the first time a link between ATR and the key regulator of the hypoxic response, HIF-1. HIF-1 stabilisation and transcriptional activity were both decreased in response to ATR inhibition. CONCLUSION: These findings suggest that ATR inhibition represents a novel strategy to target tumour cells in conditions relevant to pathophysiology and enhance the efficacy of radiotherapy.

Original publication

DOI

10.1038/bjc.2012.265

Type

Journal article

Journal

Br J Cancer

Publication Date

10/07/2012

Volume

107

Pages

291 - 299

Keywords

Ataxia Telangiectasia, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cell Hypoxia, Cell Line, Tumor, Cell Survival, DNA Damage, DNA Replication, HCT116 Cells, HeLa Cells, Histones, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Phosphorylation, Protein-Serine-Threonine Kinases, Pyrazines, Radiation Tolerance, Radiotherapy, Repressor Proteins, Signal Transduction, Sulfones, Tripartite Motif-Containing Protein 28